Pomalidomide, Ixazomib Citrate, and Dexamethasone in Treating Patients With Previously Treated Multiple Myeloma or Plasma Cell Leukemia

• Sponsor: Mayo Clinic (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02547662
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 17
• Locations: 2
• Arm: 1
• Anticipated Duration (Months): 83.7
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial studies how well pomalidomide, ixazomib citrate, and dexamethasone work in treating patients with previously treated multiple myeloma or plasma cell leukemia. Biological therapies, such as pomalidomide and dexamethasone, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pomalidomide, ixazomib citrate, and dexamethasone together may be more effective in treating multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Plasma Cell Leukemia; Plasma Cell Myeloma; Plasmacytoma	Drug: Dexamethasone; Drug: Ixazomib Citrate; Other: Laboratory Biomarker Analysis; Drug: Pomalidomide	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the confirmed response rate (>= partial response [PR]) of ixazomib citrate (ixazomib), used in combination with pomalidomide and dexamethasone in patients with previously treated multiple myeloma (MM) with extramedullary disease.

SECONDARY OBJECTIVES:

1. To determine the toxicities associated with ixazomib in combination with pomalidomide and dexamethasone in patients with previously treated MM with extramedullary disease.

2. To determine the differential response rates (biochemical versus extramedullary disease) with ixazomib in combination with pomalidomide and dexamethasone in patients with previously treated MM with extramedullary disease.

3. To determine the progression free survival following treatment with ixazomib in combination with pomalidomide and dexamethasone in patients with previously treated MM with extramedullary disease.

TERTIARY OBJECTIVES:

1. To assess the proportion of patients achieving minimal residual disease (MRD) negative status.

OUTLINE:

Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 or 6 months for up to 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Trial of Pomalidomide, Ixazomib and Dexamethasone in Patients With Multiple Myeloma With Extramedullary Disease or Plasma Cell Leukemia
• Actual Study Start Date: Dec 24, 2015
• Actual Primary Completion Date: Oct 30, 2020
• Anticipated Study Completion Date: Dec 15, 2022

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (ixazomib citrate, pomalidomide, dexamethasone) Patients receive ixazomib citrate PO on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Dexamethasone; Given PO; Other Names: Aacidexam Adexone Aknichthol Dexa Alba-Dex Alin Alin Depot Alin Oftalmico Amplidermis Anemul mono Auricularum Auxiloson Baycuten Baycuten N Cortidexason Cortisumman Decacort Decadrol Decadron Decalix Decameth Decasone R.p. Dectancyl Dekacort Deltafluorene Deronil Desamethasone Desameton Dexa-Mamallet Dexa-Rhinosan Dexa-Scheroson Dexa-sine Dexacortal Dexacortin Dexafarma Dexafluorene Dexalocal Dexamecortin Dexameth Dexamethasonum Dexamonozon Dexapos Dexinoral Dexone Dinormon Fluorodelta Fortecortin Gammacorten Hexadecadrol Hexadrol Lokalison-F Loverine Methylfluorprednisolone Millicorten Mymethasone Orgadrone Spersadex Visumetazone ; Drug: Ixazomib Citrate; Given PO; Other Names: MLN-9708 MLN9708 Ninlaro ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Pomalidomide; Given PO; Other Names: 4-Aminothalidomide Actimid CC-4047 Imnovid Pomalyst

Outcome Measures

Primary Outcome Measures

1. Confirmed Response Rate [4 years 10 months]

   A confirmed response is defined as a patient who has achieved a stringent complete response (sCR), complete response (CR), very good partial response (PR), or PR on two consecutive evaluations. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

1. Biochemical Response, Defined as a Response by Serum M-protein, Urine M-protein, or Serum Free Light Chain (FLC) Assay Parameters [4 years 10 months]

   Type of response will be differentiated as biochemical versus (vs.) extramedullary disease. The biochemical response rate will be estimated by the number of responders divided by the number of evaluable patients who have measurable disease by serum M-protein, urine M-protein, or serum FLC assay at baseline. Exact binomial confidence intervals will be calculated.

2. Extramedullary Response, Defined as a Response by Extramedullary Plasmacytoma or Plasma Cell Count Parameters [Up to 5 years]

   Type of response will be differentiated as biochemical vs. extramedullary disease. The extramedullary response rate will be estimated by the number of responders divided by the number of evaluable patients. Exact binomial confidence intervals will be calculated.

3. Incidence of Adverse Events Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [Up to 5 years]

   The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

4. Progression-free Survival [Time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years]

   The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.

Other Outcome Measures

1. Proportion of Patients Who Achieve Minimal Residual Disease (MRD) Negative Status [Up to 5 years]

   The proportion of patients who achieve MRD negative status will be estimated by the number of patients who are MRD negative divided by the total number of evaluable patients who achieve a sCR or CR. Exact binomial 95% confidence intervals for the true MRD negative rate will be calculated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Previously treated myeloma, currently with extramedullary disease (defined as plasmacytoma outside bone marrow that is not contiguous with a bone lesion) with at least one lesion that has a single diameter of >= 2 cm or plasma cell leukemia (defined as circulating plasma cells exceeding 5% of peripheral blood leukocytes or 0.5 X 10^9/L or 200 cells/150000 events by flow cytometry)

• Calculated creatinine clearance (using Cockcroft-Gault equation) >= 30 mL/min

• Absolute neutrophil count (ANC) >= 1000/mm^3

• Platelet count >= 50,000/mm^3

• Hemoglobin >= 8.0 g/dL

• Patients with measurable disease defined as at least one of the following:

• For patients with extramedullary disease (EMD) measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) or the CT portion of the positron emission tomography (PET)/CT: must have at least one lesion that has a single diameter of >= 2 cm; skin lesions can be used if the area is >= 2 cm in at least one diameter and measured with a ruler

• Plasma cell count >= 0.5 X 10^9/L or 5 percent of the peripheral blood white cells

• Plasma cell count if determined by flow cytometry, >= 200/150,000 events

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• Provide informed written consent

• Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

• All study participants must be registered into the mandatory pomalidomide (POMALYST) Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the POMALYST REMS program

• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

• Willing to provide bone marrow and blood samples for correlative research purposes

Exclusion Criteria:

• Other malignancy requiring active therapy

• EXCEPTIONS: Non-melanoma skin cancer, ductal breast carcinoma in situ (DCIS) or carcinoma-in-situ of the cervix

• NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer

• Females of childbearing potential (FCBP)* must have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours prior to prescribing pomalidomide for cycle 1 (prescriptions must be filled within 7 days as required by RevAssist [lenalidomide REMS program]), and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method; AT THE SAME TIME, at least 28 days before she starts taking pomalidomide FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; patient must follow pregnancy testing requirements as outlined in the POMALYST REMS program

• A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• Nursing women

• Men or women of childbearing potential who are unwilling to employ adequate contraception

• Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease

• Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational

• NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment

• Patient has >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period

• Major surgery =< 14 days before study registration

• Systemic treatment with strong CYP3A4 inducers (e.g. rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, gingko biloba, St. John's wort) within 7 days before registration

• Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months; Note: prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant

• Corrected QT Interval (QTc) > 470 milliseconds (msec) on a 12-lead ECG obtained during the screening period

• Note: If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG

• Known human immunodeficiency virus (HIV) positive

• Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection

• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol

• Known allergy to any of the study medications, their analogues or excipients in the various formulations

• Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing

• Diarrhea > grade 1, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading, in the absence of antidiarrheals

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905
2	Sarah Cannon Cancer Center	Nashville	Tennessee	United States	37203

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Shaji Kumar, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Apr 21, 2020

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02547662
• Other Study ID Numbers: MC1487; NCI-2015-01481; MC1487; P30CA015083
• First Posted: Sep 11, 2015
• Last Update Posted: May 23, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Leukemia, Plasma Cell; Dexamethasone; Dexamethasone acetate; Pomalidomide; Ixazomib; Ichthammol; BB 1101; Glycine

Study Results

Participant Flow

Recruitment Details	Study closed early due to recruitment concerns

Arm/Group Title	Treatment (Ixazomib Citrate, Pomalidomide, Dexamethasone)
Arm/Group Description	Patients receive ixazomib citrate PO on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dexamethasone: Given PO Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Pomalidomide: Given PO
Period Title: Overall Study
STARTED	17
COMPLETED	17
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Ixazomib Citrate, Pomalidomide, Dexamethasone)
Arm/Group Description	Patients receive ixazomib citrate PO on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dexamethasone: Given PO Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Pomalidomide: Given PO
Overall Participants	17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.2 (10.0)
Sex: Female, Male (Count of Participants)
Female	10 58.8%
Male	7 41.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	17 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	16 94.1%
More than one race	0 0%
Unknown or Not Reported	1 5.9%

Outcome Measures

1. Primary Outcome

Title	Confirmed Response Rate
Description	A confirmed response is defined as a patient who has achieved a stringent complete response (sCR), complete response (CR), very good partial response (PR), or PR on two consecutive evaluations. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	4 years 10 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Ixazomib Citrate, Pomalidomide, Dexamethasone)
Arm/Group Description	Patients receive ixazomib citrate PO on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dexamethasone: Given PO Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Pomalidomide: Given PO
Measure Participants	17
Number (95% Confidence Interval) [proportion of patients]	0.06

2. Secondary Outcome

Title	Biochemical Response, Defined as a Response by Serum M-protein, Urine M-protein, or Serum Free Light Chain (FLC) Assay Parameters
Description	Type of response will be differentiated as biochemical versus (vs.) extramedullary disease. The biochemical response rate will be estimated by the number of responders divided by the number of evaluable patients who have measurable disease by serum M-protein, urine M-protein, or serum FLC assay at baseline. Exact binomial confidence intervals will be calculated.
Time Frame	4 years 10 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Extramedullary Response, Defined as a Response by Extramedullary Plasmacytoma or Plasma Cell Count Parameters
Description	Type of response will be differentiated as biochemical vs. extramedullary disease. The extramedullary response rate will be estimated by the number of responders divided by the number of evaluable patients. Exact binomial confidence intervals will be calculated.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Incidence of Adverse Events Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Description	The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Progression-free Survival
Description	The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Time Frame	Time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Proportion of Patients Who Achieve Minimal Residual Disease (MRD) Negative Status
Description	The proportion of patients who achieve MRD negative status will be estimated by the number of patients who are MRD negative divided by the total number of evaluable patients who achieve a sCR or CR. Exact binomial 95% confidence intervals for the true MRD negative rate will be calculated.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 5 years
Arm/Group Title	Treatment (Ixazomib Citrate, Pomalidomide, Dexamethasone)
Arm/Group Description	Patients receive ixazomib citrate PO on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dexamethasone: Given PO Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Pomalidomide: Given PO
All Cause Mortality
	Treatment (Ixazomib Citrate, Pomalidomide, Dexamethasone)
	Affected / at Risk (%)	# Events
Total	3/17 (17.6%)
Serious Adverse Events
	Treatment (Ixazomib Citrate, Pomalidomide, Dexamethasone)
	Affected / at Risk (%)	# Events
Total	5/17 (29.4%)
Blood and lymphatic system disorders
Anemia	1/17 (5.9%)	1
General disorders
Death NOS	1/17 (5.9%)	1
Infections and infestations
Infections and infestations - Oth spec	1/17 (5.9%)	1
Lung infection	3/17 (17.6%)	4
Upper respiratory infection	1/17 (5.9%)	1
Injury, poisoning and procedural complications
Ankle fracture	1/17 (5.9%)	1
Investigations
Alanine aminotransferase increased	1/17 (5.9%)	1
Aspartate aminotransferase increased	1/17 (5.9%)	1
Creatinine increased	1/17 (5.9%)	1
Lymphocyte count decreased	1/17 (5.9%)	1
Platelet count decreased	3/17 (17.6%)	3
Musculoskeletal and connective tissue disorders
Back pain	1/17 (5.9%)	1
Generalized muscle weakness	1/17 (5.9%)	1
Neck pain	1/17 (5.9%)	1
Pain in extremity	1/17 (5.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, mal, uncpec - Oth spec	1/17 (5.9%)	1
Nervous system disorders
Encephalopathy	1/17 (5.9%)	1
Intracranial hemorrhage	1/17 (5.9%)	1
Psychiatric disorders
Confusion	2/17 (11.8%)	2
Respiratory, thoracic and mediastinal disorders
Cough	1/17 (5.9%)	1
Dyspnea	1/17 (5.9%)	2
Hypoxia	2/17 (11.8%)	2
Respiratory failure	1/17 (5.9%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Ixazomib Citrate, Pomalidomide, Dexamethasone)
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
Anemia	16/17 (94.1%)	47
Eye disorders
Eye disorders - Other, specify	1/17 (5.9%)	6
Gastrointestinal disorders
Constipation	10/17 (58.8%)	55
Diarrhea	5/17 (29.4%)	6
Nausea	9/17 (52.9%)	13
General disorders
Edema limbs	2/17 (11.8%)	3
Fatigue	14/17 (82.4%)	102
Pain	1/17 (5.9%)	1
Infections and infestations
Urinary tract infection	1/17 (5.9%)	1
Injury, poisoning and procedural complications
Ankle fracture	1/17 (5.9%)	4
Investigations
Creatinine increased	7/17 (41.2%)	39
Lymphocyte count decreased	4/17 (23.5%)	7
Neutrophil count decreased	13/17 (76.5%)	40
Platelet count decreased	12/17 (70.6%)	41
White blood cell decreased	13/17 (76.5%)	30
Metabolism and nutrition disorders
Hyperglycemia	1/17 (5.9%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/17 (5.9%)	4
Pain in extremity	1/17 (5.9%)	2
Nervous system disorders
Peripheral motor neuropathy	2/17 (11.8%)	2
Peripheral sensory neuropathy	10/17 (58.8%)	79
Tremor	1/17 (5.9%)	2
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/17 (5.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.